Natural IgM Sensing of DAMPS The concept of DAMPS (damage associated molecular patterns) which are self-antigens that induce acute inflammation is well established. The general principle is that trauma, infection or other forms of stress such as hypoxia leads to exposure of highly conserved nuclear or cytoplasmic antigens that trigger an innate response. Both intracellular and extracellular sensors of DAMPS have been identified. Of the latter, natural antibodies, produced by B-1 cells, represent a major set of recognition proteins. Although produced by B lymphocytes, natural antibodies act as innate receptors as they have evolved to bind highly conserved self-antigens or neoepitopes. Binding of self-antigen by natural antibodies following hypoxic stress, i.e. reperfusion, induces a complement-dependent inflammatory response leading to severe and often fatal disease as observed in multiple tissues such as intestinal, skeletal muscle, heart and brain. A broader role in inflammation is suggested by their enhancement of injury in sites of inflammation such as the synovium in arthritis and retina in macular degeneration. Despite the potential importance of natural antibodies in human disease, fundamental unanswered questions remain. To address this barrier, we propose to construct a murine model in which the B cells express an immunoglobulin receptor specific for a known reperfusion injury neoepitope, i.e. non-muscle myosin heavy chain II and relevant clonotypic monoclonal antibodies. In addition, we will test the hypothesis that B-1 cells specific for IR antigen migrate into inflamed tissues where they modify the response. The availability of the new animal model and anti-clonotypic reagents can be used as proof of concept for support of more in depth studies in the future to move this important field forward.